Rearrangement reactions of taxanes: structural modifications of 10-deacetylbaccatin III.

Chemistry and Structure—Activity Relationships of Taxoids with Modified Skeletons

“…Molecular modeling of compound 19 showed that the hydroxyl at carbon 15 is very close to the C-9 keto group, allowing the formation of an hemiacetal intermediate which reacts with the carbonate protecting group at C-10. Similar rearrangements have been previously noticed with the diprotected derivative of 10-deacetylbaccatin III (34). In order to avoid this intramolecular rearrangement, docetaxel was treated directly with trifluoroacetic acid giving the Α-ring contracted docetaxel derivative 23 (Scheme 3).…”

“…Similar to 18, the Α-ring contracted analogue 23 was as active in the microtubule depolymerization assay as paclitaxel, but was devoid of cytotoxicity (34,36). Conformational study of compounds 18 and 23 shows that the structures of the taxane core and of the side chain are close to that of docetaxel 2 (36).…”

“…As with other terpenoids, Wagner-Meerwein rearrangement occurs to the Α-ring of taxoids bearing a tertiary hydroxyl group at C-l (33)(34)(35). Kingston and his collaborators (33) found that treatment of the 7, 2'-(9-diprotected paclitaxel derivative with mesyl chloride and subsequent deprotection led to the Α-ring contracted derivative 18 which possesses an antitubulin activity similar to that of paclitaxel (33).…”

“…Under acidic conditions (aqueous trifluoroacetic acid), the diprotected 10-deacetyl baccatin ΙΠ derivative 5a led mainly to the hydroxyisopropyl derivative 19 (34).…”

“…Cleavage of the vicinal acetyl oxetane occurs by intramolecular attack of the acetyl group upon the methylene at carbon 5. The reaction was carried out with various electrophilic reagents from paclitaxel 1 (33,40), baccatin III 3b (40) and 10-deacetylbaccatin III 3a (34). The use of tin tetrachloride gave the best yield of opened oxetane derivatives (36,40).…”